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Fasting for >8 h, as previously required for lipid profiles, normally only occurs a few hours before breakfast. By contrast, the nonfasting state predominates most of a 24-h cycle and better captures atherogenic lipoprotein levels. Plasma contains atherogenic lipoproteins of hepatic origin in the fasting state and additionally those of intestinal origin in the nonfasting state. Maximal mean changes for random, nonfasting versus fasting levels are +26 mg/dl for triglycerides, -8 mg/dl for total cholesterol, -8 mg/dl for low-density lipoprotein cholesterol, +8 mg/dl for remnant cholesterol, and -8 mg/dl for non-high-density lipoprotein cholesterol; lipoprotein(a), apolipoprotein B, and high-density lipoprotein cholesterol are largely unaffected. For patients, laboratories, and clinicians alike, nonfasting lipid profiles represent a simplification without negative implications for prognostic, diagnostic, and therapeutic options for cardiovascular disease prevention. Several societies' guidelines and statements in Denmark, the United Kingdom, Europe, Canada, Brazil, and the United States endorse nonfasting lipid profiles. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide and challenges the capacity of health care systems globally. Atherosclerosis is the underlying pathophysiological entity in two-thirds of patients with CVD. When considering that atherosclerosis develops over decades, there is potentially great opportunity for prevention of associated events such as myocardial infarction and stroke. Subclinical atherosclerosis has been identified in its early stages in young individuals; however, there is no consensus on how to prevent progression to symptomatic disease. Given the growing burden of CVD, a paradigm shift is required—moving from late management of atherosclerotic CVD to earlier detection during the subclinical phase with the goal of potential cure or prevention of events. Studies must focus on how precision medicine using imaging and circulating biomarkers may identify atherosclerosis earlier and determine whether such a paradigm shift would lead to overall cost savings for global health. [Display omitted] • Early-stage subclinical atherosclerosis can be identified in young individuals, but evidence-based strategies are needed to prevent progression of disease and clinical events. • Precision medicine using imaging and circulating biomarkers could facilitate early identification of atherosclerosis and the development of curative interventions. • A paradigm shift based on these principles could reduce the global burden of CVD with enormous implications for population health. [ABSTRACT FROM AUTHOR]

Elevated remnant cholesterol and low-grade inflammation each cause atherosclerotic cardiovascular disease (ASCVD); however, it is unknown whether joint elevation of both factors confers the highest risk. We tested the hypothesis that dual elevated remnant cholesterol and low-grade inflammation marked by elevated C-reactive protein is associated with the highest risk of myocardial infarction, ASCVD, and all-cause mortality. The Copenhagen General Population Study randomly recruited white Danish individuals aged 20–100 years in 2003–2015 and followed them for a median 9.5 years. ASCVD was cardiovascular mortality, myocardial infarction, stroke, and coronary revascularization. In 103,221 individuals, we observed 2,454 (2.4%) myocardial infarctions, 5,437 (5.3%) ASCVD events, and 10,521 (10.2%) deaths. The hazard ratios increased with each of stepwise higher remnant cholesterol and stepwise higher C-reactive protein. In individuals with the highest tertile of both remnant cholesterol and C-reactive protein compared to individuals with the lowest tertile of both, the multivariable adjusted hazard ratios were 2.2 (95%CI:1.9–2.7) for myocardial infarction, 1.9 (1.7–2.2) for ASCVD, and 1.4 (1.3–1.5) for all-cause mortality. Corresponding values for only the highest tertile of remnant cholesterol were 1.6 (1.5–1.8), 1.4 (1.3–1.5), and 1.1 (1.0–1.1), and those for only the highest tertile of C-reactive protein were 1.7 (1.5–1.8), 1.6 (1.5–1.7), and 1.3 (1.3–1.4), respectively. There was no statistical evidence for interaction between elevated remnant cholesterol and elevated C-reactive protein on risk of myocardial infarction (p = 0.10), ASCVD (p = 0.40), or all-cause mortality (p = 0.74). Dual elevated remnant cholesterol and C-reactive protein confers the highest risk of myocardial infarction, ASCVD, and all-cause mortality, that is, compared to either of these two factors individually. [Display omitted] • Dual elevated remnant-C and CRP was associated with the highest risk of ASCVD. • ASCVD risk is particularly relevant if remnant-C is ≥ 0.8 mmol/L and CRP ≥1.5 mg/L. • ASCVD risk was double in the highest tertile of both compared to the lowest. [ABSTRACT FROM AUTHOR]

Background Werner syndrome, a premature genetic aging syndrome, shares many clinical features reminiscent of normal physiological aging, and ischemic vascular disease is a frequent cause of death. We tested the hypothesis that genetic variation in the WRN gene was associated with risk of ischemic vascular disease in the general population. Methods We included 58,284 participants from two general population cohorts, the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS). Of these, 6,312 developed ischemic vascular disease during follow-up. In the CCHS ( n = 10,250), we genotyped all non-synonymous variants in WRN with reported minor allele frequencies ≥ 0.5% in Caucasians. Second, variants which were associated with ischemic vascular disease in the CCHS or in previous studies, were genotyped in the CGPS ( n = 48,034). Results A total of 11 non-synonymous variants were identified in the CCHS. In C1367R (rs1346044) TT homozygotes versus CC/CT, hazard ratios for ischemic stroke were 1.09 (95% confidence interval: 0.95–1.24; P = 0.22) in the CCHS, 1.16 (1.00–1.33; P = 0.04) in the CGPS, and 1.12 (1.01–1.23; P = 0.02) in studies combined (CCHS + CGPS), with similar trends for ischemic cerebrovascular disease ( P = 0.06). In meta-analyses including 59,190 individuals in 5 studies, the hazard ratio for ischemic stroke for C1367R TT homozygotes versus CC/CT was 1.14 (1.04–1.25; P = 0.008). Conclusions This study suggests that common genetic variation in WRN is associated with increased risk of ischemic stroke in the general population. [ABSTRACT FROM AUTHOR]

It is unclear whether elevated low-density lipoprotein (LDL) triglycerides are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). This study tested the hypothesis that elevated LDL triglycerides are associated with an increased risk of ASCVD and of each ASCVD component individually. The study investigators used the Copenhagen General Population Study, which measured LDL triglycerides in 38,081 individuals with a direct automated assay (direct LDL triglycerides) and in another 30,208 individuals with nuclear magnetic resonance (NMR) spectroscopy (NMR LDL triglycerides). Meta-analyses aggregated the present findings with previously reported results. During a median follow-up of 3.0 and 9.2 years, respectively, 872 and 5,766 individuals in the 2 cohorts received a diagnosis of ASCVD. Per 0.1 mmol/L (9 mg/dL) higher direct LDL triglycerides, HRs were 1.26 (95% CI: 1.17-1.35) for ASCVD, 1.27 (95% CI: 1.16-1.39) for ischemic heart disease, 1.28 (95% CI: 1.11-1.48) for myocardial infarction, 1.22 (95% CI: 1.08-1.38) for ischemic stroke, and 1.38 (95% CI: 1.21-1.58) for peripheral artery disease. Corresponding HRs for NMR LDL triglycerides were 1.26 (95% CI: 1.20-1.33), 1.33 (95% CI: 1.25-1.41), 1.41 (95% CI: 1.31-1.52), 1.13 (95% CI: 1.05-1.23), and 1.26 (95% CI: 1.10-1.43), respectively. The foregoing results were not entirely statistically explained by apolipoprotein B levels. In meta-analyses for the highest quartile vs the lowest quartile of LDL triglycerides, random-effects risk ratios were 1.50 (95% CI: 1.35-1.66) for ASCVD (4 studies; 71,526 individuals; 8,576 events), 1.62 (95% CI: 1.37-1.93) for ischemic heart disease (6 studies; 107,538 individuals; 9,734 events), 1.30 (95% CI: 1.13-1.49) for ischemic stroke (4 studies; 78,026 individuals; 4,273 events), and 1.53 (95% CI: 1.29-1.81) for peripheral artery disease (4 studies; 107,511 individuals; 1,848 events). Elevated LDL triglycerides were robustly associated with an increased risk of ASCVD and of each ASCVD component individually in 2 prospective cohort studies and in meta-analyses of previous and present studies combined. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Guidelines recommend initiating primary prevention for atherosclerotic cardiovascular disease (ASCVD) with statins based on absolute ASCVD risk assessment. Recently, alternative trial-based and hybrid approaches were suggested for statin treatment eligibility.Objectives: This study compared these approaches in a direct head-to-head fashion in a contemporary population.Methods: The study used the CGPS (Copenhagen General Population Study) with 37,892 subjects aged 40 to 75 years recruited in 2003 to 2008, all free of ASCVD, diabetes, and statin use at baseline.Results: Among the population studied, 42% were eligible for statin therapy according to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) risk assessment and cholesterol treatment guidelines approach, versus 56% with the trial-based approach and 21% with the hybrid approach. Among these statin-eligible subjects, the ASCVD event rate per 1,000 person-years was 9.8, 6.8, and 11.2, respectively. The ACC/AHA-recommended absolute risk score was well calibrated around the 7.5% 10-year ASCVD risk treatment threshold and discriminated better than the trial-based or hybrid approaches. Compared with the ACC/AHA risk-based approach, the net reclassification index for eligibility for statin therapy among 40- to 75-year-old subjects from the CGPS was -0.21 for the trial-based approach and -0.13 for the hybrid approach.Conclusions: The clinical performance of the ACC/AHA risk-based approach for primary prevention of ASCVD with statins was superior to the trial-based and hybrid approaches. Our results indicate that the ACC/AHA guidelines will prevent more ASCVD events than the trial-based and hybrid approaches, while treating fewer people compared with the trial-based approach. [ABSTRACT FROM AUTHOR]

Background: Women with previous preeclampsia have an increased risk of coronary artery disease later in life.Objectives: This study aimed to determine the prevalence of coronary atherosclerosis in younger women with previous preeclampsia in comparison with women from the general population.Methods: Women aged 40-55 years with previous preeclampsia were matched 1:1 on age and parity with women from the general population. Participants completed an extensive questionnaire, a clinical examination, and a coronary computed tomography angiography (CTA). The main study outcome was the prevalence of any coronary atherosclerosis on coronary CTA or a calcium score >0 in case of a nondiagnostic coronary CTA.Results: A total of 1,417 women, with a mean age of 47 years, were included (708 women with previous preeclampsia and 709 control subjects from the general population). Women with previous preeclampsia were more likely to have hypertension (284 [40.1%] vs 162 [22.8%]; P < 0.001), dyslipidemia (338 [47.7%] vs 296 [41.7%]; P = 0.023), diabetes mellitus (24 [3.4%] vs 8 [1.1%]; P = 0.004), and high body mass index (27.3 ± 5.7 kg/m2 vs 25.0 ± 4.2 kg/m2; P < 0.001). Cardiac computed tomography was performed in all women. The prevalence of any coronary atherosclerosis was higher in the preeclampsia group (193 [27.4%] vs 141 [20.0%]; P = 0.001) with an OR: 1.41 (95% CI: 1.08-1.85; P = 0.012) after adjustment for age, dyslipidemia, diabetes mellitus, smoking, body mass index, menopause, and parity.Conclusions: Younger women with previous preeclampsia had a slightly higher prevalence of coronary atherosclerosis compared with age- and parity-matched women from the general population. Preeclampsia remained an independent risk factor after adjustment for traditional cardiovascular risk factors. (The CoPenHagen PREeClampsia and cardIOvascUlar diSease study [CPH-PRECIOUS]; NCT03949829). [ABSTRACT FROM AUTHOR]

Abstract: This review focuses on remnant cholesterol as a causal risk factor for ischemic heart disease (IHD), on its definition, measurement, atherogenicity, and levels in high risk patient groups; in addition, present and future pharmacological approaches to lowering remnant cholesterol levels are considered. Observational studies show association between elevated levels of remnant cholesterol and increased risk of cardiovascular disease, even when remnant cholesterol levels are defined, measured, or calculated in different ways. In-vitro and animal studies also support the contention that elevated levels of remnant cholesterol may cause atherosclerosis same way as elevated levels of low-density lipoprotein (LDL) cholesterol, by cholesterol accumulation in the arterial wall. Genetic studies of variants associated with elevated remnant cholesterol levels show that an increment of 1mmol/L (39mg/dL) in levels of nonfasting remnant cholesterol associates with a 2.8-fold increased risk of IHD, independently of high-density lipoprotein cholesterol levels. Results from genetic studies also show that elevated levels of remnant cholesterol are causally associated with both low-grade inflammation and IHD. However, elevated levels of LDL cholesterol are associated with IHD, but not with low-grade inflammation. Such results indicate that elevated LDL cholesterol levels cause atherosclerosis without a major inflammatory component, whereas an inflammatory component of atherosclerosis is driven by elevated remnant cholesterol levels. Post-hoc subgroup analyses of randomized trials using fibrates in individuals with elevated triglyceride levels, elevated remnant cholesterol levels, show a benefit of lowering triglycerides or remnant cholesterol levels; however, large randomized trials with the primary target of lowering remnant cholesterol levels are still missing. [Copyright &y& Elsevier]

Background: Plasma apolipoprotein B (apoB) is a composite measure of all apoB-containing lipoproteins causing atherosclerotic cardiovascular disease; however, it is unclear which fraction of risk is explained by cholesterol and triglycerides, respectively, in very low-density lipoproteins (VLDLs).Objectives: The authors tested the hypothesis that VLDL cholesterol and triglycerides each explain part of the myocardial infarction risk from apoB-containing lipoproteins.Methods: Nested within 109,751 individuals from the Copenhagen General Population Study, the authors examined 25,480 subjects free of lipid-lowering therapy and myocardial infarction at study entry. All had measurements of plasma apoB (quantitating number of apoB-containing lipoproteins) and cholesterol and triglyceride content of VLDL, intermediate-density lipoproteins (IDLs), and low-density lipoproteins (LDLs).Results: During a median 11 years of follow-up, 1,816 were diagnosed with myocardial infarction. Per 1-mmol/l higher levels, multivariable-adjusted hazard ratios for myocardial infarction were 2.07 (95% confidence interval [CI]: 1.81 to 2.36) for VLDL cholesterol, 1.19 (95% CI: 1.14 to 1.25) for VLDL triglycerides, 5.38 (95% CI: 3.73 to 7.75) for IDL cholesterol, and 1.86 (95% CI: 1.62 to 2.14) for LDL cholesterol. Per 1-g/l higher plasma apoB, the corresponding value was 2.21 (95% CI: 1.90 to 2.58). In a step-up Cox regression, risk factors for myocardial infarction entered by importance as VLDL cholesterol, systolic blood pressure, smoking, and IDL + LDL cholesterol, whereas VLDL triglycerides did not enter the model. VLDL cholesterol explained 50% and IDL + LDL cholesterol 29% of the risk of myocardial infarction from apoB-containing lipoproteins, whereas VLDL triglycerides did not explain risk.Conclusions: VLDL cholesterol explained one-half of the myocardial infarction risk from elevated apoB-containing lipoproteins, whereas VLDL triglycerides did not explain risk. [ABSTRACT FROM AUTHOR]

During fat tolerance tests, plasma triglycerides increase while high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and intermediate-density lipoprotein (IDL) cholesterol decrease. However, it is unknown whether triglyceride content increases and cholesterol content decreases in HDL and LDL + IDL fractions following normal meals in the general population. Therefore, we tested the hypothesis that triglyceride content increases while cholesterol content decreases in HDL and LDL + IDL fractions following normal meals. In this cross-sectional study, we included 25,656 individuals aged 20–100 years, all without lipid-lowering therapy at examination and selected for metabolomic profiling from the Copenhagen General Population Study. Triglyceride and cholesterol content of 14 lipoprotein fractions weas measured using nuclear magnetic resonance (NMR) spectroscopy. Time since last meal was recorded by the examiner immediately before blood sampling. Following normal meals in age and sex-adjusted analyses and when compared with fasting levels, plasma triglycerides were higher for up to 5–6 h, and triglyceride content was higher for up to 6–7 h in HDL fractions, for up to 6–7 h in LDL + IDL fractions, and for up to 5–6 h in very-low-density lipoprotein (VLDL) fractions. Further, plasma cholesterol was lower for up to 2–3 h, and cholesterol content was lower for up to 0–1 h in HDL fractions and for up to 4–5 h in LDL + IDL fractions, while cholesterol content was higher for up to 4–5 h in VLDL fractions. Following normal meals, triglyceride content increases while cholesterol content decreases in HDL and LDL + IDL fractions. [Display omitted] • Following normal meals, triglyceride content increases in HDL and LDL + IDL fractions. • Following normal meals, cholesterol content decreases in HDL and LDL + IDL fractions. • Following normal meals, cholesterol content decreases in the smallest HDL fractions. • Following normal meals, cholesterol content increases in the largest VLDL fractions. • Results were similar in women and men, and in individuals with low and high BMI. [ABSTRACT FROM AUTHOR]

Increased concentrations of calculated remnant cholesterol in triglyceride-rich lipoproteins are observationally and genetically, causally associated with increased risk of ischemic heart disease; however, when measured directly, the fraction of plasma cholesterol present in remnant particles is unclear. We tested the hypothesis that a major fraction of plasma cholesterol is present in remnant lipoproteins in individuals in the general population. We examined 9293 individuals from the Copenhagen General Population Study using nuclear magnetic resonance spectroscopy measurements of total cholesterol, free- and esterified cholesterol, triglycerides, phospholipids, and particle concentration. Fourteen subclasses of decreasing size and their lipid constituents were analysed: six subclasses were very low-density lipoprotein (VLDL), one intermediate-density lipoprotein (IDL), three low-density lipoprotein (LDL), and four subclasses were high-density lipoprotein (HDL). Remnant lipoproteins were VLDL and IDL combined. Mean nonfasting cholesterol concentration was 1.84 mmol/L (72 mg/dL) for remnants, 2.01 mmol/L (78 mg/dL) for LDL, and 1.83 mmol/L (71 mg/dL) for HDL, equivalent to remnants containing 32% of plasma total cholesterol. Of 14 lipoprotein subclasses, large LDL and IDL were the ones containing most of plasma cholesterol. The plasma concentration of remnant cholesterol was from ∼1.4 mmol/L (54 mg/dL) at age 20 to ∼1.9 mmol/L (74 mg/dL) at age 60. Corresponding values for LDL cholesterol were from ∼1.5 mmol/L (58 mg/dL) to ∼2.1 mmol/L (81 mg/dL). Using direct measurements, one third of total cholesterol in plasma was present in remnant lipoproteins, that is, in the triglyceride-rich lipoproteins IDL and VLDL. Image 1 • Using NMR, a third of plasma cholesterol was present in remnant lipoproteins. • Of 14 lipoprotein subclasses, large LDL and IDL were containing most cholesterol. • Directly measured remnant cholesterol was highest in older individuals. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to test the hypothesis that elevated nonfasting remnant cholesterol is a causal risk factor for ischemic heart disease independent of reduced high-density lipoprotein (HDL) cholesterol. Background: Elevated remnant cholesterol is associated with elevated levels of triglyceride-rich lipoproteins and with reduced HDL cholesterol, and all are associated with ischemic heart disease. Methods: A total of 73,513 subjects from Copenhagen were genotyped, of whom 11,984 had ischemic heart disease diagnosed between 1976 and 2010. Fifteen genetic variants were selected, affecting: 1) nonfasting remnant cholesterol alone; 2) nonfasting remnant cholesterol and HDL cholesterol combined; 3) HDL cholesterol alone; or 4) low-density lipoprotein (LDL) cholesterol alone as a positive control. The variants were used in a Mendelian randomization design. Results: The causal odds ratio for a 1 mmol/l (39 mg/dl) genetic increase of nonfasting remnant cholesterol was 2.8 (95% confidence interval [CI]: 1.9 to 4.2), with a corresponding observational hazard ratio of 1.4 (95% CI: 1.3 to 1.5). For the ratio of nonfasting remnant cholesterol to HDL cholesterol, corresponding values were 2.9 (95% CI: 1.9 to 4.6) causal and 1.2 (95% CI 1.2 to 1.3) observational for a 1-U increase. However, for HDL cholesterol, corresponding values were 0.7 (95% CI: 0.4 to 1.4) causal and 1.6 (95% CI: 1.4 to 1.7) observational for a 1 mmol/l (39 mg/dl) decrease. Finally, for LDL cholesterol, corresponding values were 1.5 (95% CI: 1.3 to 1.6) causal and 1.1 (95% CI: 1.1 to 1.2) observational for a 1 mmol/l (39 mg/dl) increase. Conclusions: A nonfasting remnant cholesterol increase of 1 mmol/l (39 mg/dl) is associated with a 2.8-fold causal risk for ischemic heart disease, independent of reduced HDL cholesterol. This implies that elevated cholesterol content of triglyceride-rich lipoprotein particles causes ischemic heart disease. However, because pleiotropic effects of the genetic variants studied cannot be totally excluded, these findings need to be confirmed using additional genetic variants and/or randomized intervention trials. [Copyright &y& Elsevier]

Objectives: The purpose of this study was to test whether elevated nonfasting glucose levels associate with and cause ischemic heart disease (IHD) and myocardial infarction (MI). Background: Elevated fasting plasma glucose levels associate with increased risk of IHD, but whether this is also true for nonfasting levels and whether this is a causal relationship is unknown. Methods: Using a Mendelian randomization approach, we studied 80,522 persons from Copenhagen, Denmark. Of those, IHD developed in 14,155, and MI developed in 6,257. Subjects were genotyped for variants in GCK (rs4607517), G6PC2 (rs560887), ADCY5 (rs11708067), DGKB (rs2191349), and ADRA2A (rs10885122) associated with elevated fasting glucose levels in genome-wide association studies. Results: Risk of IHD and MI increased stepwise with increasing nonfasting glucose levels. The hazard ratio for IHD in subjects with nonfasting glucose levels ≥11 mmol/l (≥198 mg/dl) versus <5 mmol/l (<90 mg/dl) was 6.9 (95% confidence interval [CI]: 4.2 to 11.2) adjusted for age and sex, and 2.3 (95% CI: 1.3 to 4.2) adjusted multifactorially; corresponding values for MI were 9.2 (95% CI: 4.6 to 18.2) and 4.8 (95% CI: 2.1 to 11.2). Increasing number of glucose-increasing alleles was associated with increasing nonfasting glucose levels and with increased risk of IHD and MI. The estimated causal odds ratio for IHD and MI by instrumental variable analysis for a 1-mmol/l (18-mg/dl) increase in nonfasting glucose levels due to genotypes combined were 1.25 (95% CI: 1.03 to 1.52) and 1.69 (95% CI: 1.28 to 2.23), and the corresponding observed hazard ratio for IHD and MI by Cox regression was 1.18 (95% CI: 1.15 to 1.22) and 1.09 (95% CI: 1.07 to 1.11), respectively. Conclusions: Like common nonfasting glucose elevation, plasma glucose-increasing polymorphisms associate with increased risk of IHD and MI. These data are compatible with a causal association. [Copyright &y& Elsevier]